PROJECT SUMMARY/ABSTRACT Despite reductions in combustible cigarette consumption rates, approximately 5.6 million American children are expected to die prematurely from a smoking-related illness unless rates continue to decline.1 This statistic is particularly staggering when considering that electronic nicotine delivery systems (ENDS) are increasing in popularity.2 Prospective studies identifying antecedents and consequences of ENDS use, especially among underrepresented racial minority groups, are paramount. Furthermore, clarifying the negative health effects of ENDS use on the developing adolescent brain is critical. Targeting populations demonstrating the highest rates of ENDS use, including Hispanic/Latino and Black/African American high school students, will have the greatest impact on reducing mortality and morbidity from tobacco-related illness. This project's aims are three-fold. First, we will identify risk and protective factors that predict the onset of ENDS among high-risk adolescents without prior substance use, and whether or not they also predict cigarette onset. We will characterize factors specific to ENDS (e.g., flavoring, perceptions of harm), as well as general factors associated with substance use initiation including personality and social contexts. Second, given mixed findings on the role of ENDS as a potential gateway drug, we will also determine whether ENDS-users are more likely to transition to cigarettes, marijuana, and/or polysubstance use compared to non-users. ENDS specific factors, as well as factors associated with substance use escalation, including psychopathology and nicotine dependence, will be examined. Third, we will delineate neurobiological differences across adolescents having initiated ENDS use with those that have not using magnetic resonance imaging. We will examine whether ENDS use, similar to cigarette use, is linked with reduced cortical thickness in the ventromedial prefrontal cortex and insula and altered functional activity in the striatum during reward processing. We will also determine if similar brain alterations precede use by scanning adolescents prior to nicotine exposure. This is important to delineate the neurobiological trajectories that may place an adolescent onto a path for addiction. We will focus on Hispanic/Latino and Black/African American high school students as ENDS use is highest among this group.3,4 Identifying risk and protective factors specific to this population will help avert tobacco use disparities. Furthermore, although a majority of healthcare providers have heard of ENDS, most report knowing very little about these products including potential negative health consequences. Empirical evidence regarding the onset, potential transitions, and negative consequences on the brain of ENDS use is critical to help clinicians improve prevention programming and assist policy makers in deciding how to continue regulating these products. By identifying key modifiable targets, this work will help healthcare professionals improve routine screenings, substance use counseling, and preventive interventions.